Authors

Document Type

Conference Proceeding

Publication Date

1984

Abstract

We have investigated the metabolism and disposition in rodents of OM, a new anthracycline antibiotic entering clinical trials. OM, dissolved in 0.01 M glucuronic acid, was administered iv to mice (10 mg/kg). At specified times after injection, mice were killed, and OM and metabolites were essayed in plasma and organs by HPLC (C8 column, mobile phase : acetic acid, methane sulfonic acid, acetonitrile; detection by fluorescence). In plasma, OM declined in triexponential fashion. The terminal half-life was 10.7 hr; the area under the curve (AUC) was 10.02 μMxhr; the apparent VC was 0.4 L/m2, and the systemic clearance, 92.2 ml/min/m2. A metabolite, that had the HPLC characteristics of N-demethyl menogarol, was seen during the first 30 minutes after injection. OM distributed extensively to tissues. OM concentration was initially the greatest in the lungs (peak OM concentration : 1420 nmol/g); no OM was detected in the brain. The terminal half-life was the shortest in heart and liver, intermediate in lungs and skeletal muscle, and the longest in spleen, kidneys, and pancreas. The OM-AUC in organs was the highest for the lungs (605 μMxhr), spleen (522 μMxhr), and the pancreas (430 μMxhr), and the smallest in heart (33 μMxhr) and the liver (60 μMxhr). Kidneys and skeletal muscle had intermediate values. In liver, 2 metabolites, one of which had HPLC characteristics of N-demethyl menogarol, were seen. In other organs, the same metabolites were seen later and in smaller quantities. In hamsters harboring a well differentiated pancreatic tumor and treated with OM, the tumor AUC was 40% of the pancreas AUC. Our data show that, in plasma, OM behaves in first- order fashion; tissue distribution is extensive and metabolites are formed in significant amounts.

Comments

Presented at the 4th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Brussels, Belgium.